(523b) Crystallization Design: A Case Study on an Active Pharmaceutical Ingredient (API)

Crystallization serves as a key separation and purification technique to deliver material of specified quality, form and powder properties for downstream processing in the pharmaceutical industry. This case study will focus on the systematic development of an API crystallization designed to: (1) simplify the current process to deliver the desired form, (2) improve the powder properties through particle morphology manipulation to meet the target material profile (TMP) and (3) control in-process impurities.

Early attempts to generate the desired form relied on a multi-step (three isolation) transformation starting from the free acid, to the addition of the counter-ion and finally hydration by a slurry to slurry conversion. Although this process successfully provided the desired form, the laborious sequence and poor powder properties were prohibitive for long-term use. As a result, further development was necessary to identify a superior alternative.

This case study will review the steps taken to simplify the process through elimination of one isolation, to improve the particle morphology from poor handling thin needles/plates to columnar/rod-like particles and finally to implement control strategies to ensure acceptable purity. The discussion will begin with an analysis of solvent screening results and viable bases and highlight the decision process to achieve suitable form, morphology and yield. The solvent and base system selected was optimized for particle morphology and powder properties through careful mapping of the crystallization space guided by process analytical technology (PAT). Understanding of the super-saturation profile allowed for determination of the optimal seed point, seed type, and anti-solvent addition rates to control growth and nucleation. Finally, strategies implemented to control the formation of in-process impurities will be reviewed.